Multifaceted endovascular stent coating for preventing restenosis

ABSTRACT

This invention deals with a carboxyl-bearing, amphiphilic, solid copolyester stent coating composition for multifaceted prevention of vascular restenosis through a plurality of physicopharmacological modes. The composition includes one or more bioactive compounds and a copolymerization product of polyalkylene glycol, end-grafted with one or more cyclic monomer and treated further to introduce carboxyl-bearing end- or side-groups. The invention also deals with bioactive agents in an ionically conjugated form. The present coating may be applied to a metallic or an absorbable polymeric stent for use in preventing vascular restenosis.

This application claims the benefit of prior provisional application,U.S. Ser. No. 60/375,182, filed Apr. 24, 2002.

FIELD OF THE INVENTION

This invention relates to biomedical applications of an amphiphilic,absorbable copolyester stent coating, which includes a bioactive agentto provide a multifaceted composition for preventing vascular restenosisthrough the simultaneous display of more than two of the key propertiesassociated with rendering metallic and polymeric endovascular stentseffective in preventing or minimizing restenosis.

BACKGROUND OF THE INVENTION

Cardiovascular and lumenal stents are highly effective in the treatmentof heart disease and other vascular conditions by the dilation andretention of constricted vessels or bodily conduits. However, theirinsertion may induce undesirable bodily reactions such as inflammation,infections, thrombosis or blood clots, restenosis, and proliferation ofcell growth that occludes the passageway and may incur the need foradditional surgery. Pharmaceutical drugs and compounds may assist inpreventing these conditions, although they may be required in large oralor intravenous doses with stringent intake or injection timetables toincrease their efficacy.

Pharmaceutical compounds may be coated directly on the stent to providea preferable point-of-use drug delivery system, but these coatings mustbe bioengineered to control the release of sometimes highly potent andpotentially toxic drugs. Timed-release attributes of a coating must beincorporated to avoid clinically unacceptable premature releases oftoxic levels of potent drugs. Biocompatible, biodegradable polymers forvarious biomedical applications such as those used in sutures and tissueengineering have been described in “Functionalized Polyester GraftCopolymers,” Hrkach, et al., U.S. Pat. No. 5,654,381, issued Aug. 5,1997. Drug-polymers based on polylactide and drug mixtures in particleor pellet form to provide timed-release delivery are described in“Polylactide-Drug Mixtures,” Boswell, et al., U.S. Pat. No. 3,773,919,issued Nov. 20, 1973, or in a spray form as described in“Polylactide-Drug Mixtures for Topical Application,” Scribner, et al.,U.S. Pat. No. 3,755,558, issued Aug. 28, 1973.

These developments in pharmaceutical coatings, however, have limitedcontrol over the delivery of the drug and versatility in the types ofdrugs to be delivered and their pharmacodynamics. The delivery of thedrug may be too fast, ineffective and possibly toxic, or too slow andineffective. The drug coating may not stick or adhere. The drug polymercoatings should coat the stent framework without cracking, peeling ordelaminating, particularly when the stent is expanded duringinstallation. The coating should not fall off, crack, fracture,crystallize or melt during processing, sterilizing, or installing. Insome cases, a rapid delivery of a drug may be needed immediatelyfollowing surgery, followed by a steady delivery of the drug at a lesserrate over an extended period of time. Because there is need for the invivo delivery of more than one drug, delivery of one or multiple drugtypes from a deployed, coated stent with variable elution rates isdesirable. One drug type in a polymer coating may elute faster thananother drug type in the same polymer, thus methods of modulating a drugwithout impacting its bioactive moiety are desirable.

In spite of the broad coverage of the prior art on the use endovascularstents for the prevention of restenosis entailing many types of stentpolymeric barrier coatings and bioactive agents for inhibitingrestenosis, integrating the role of both components into aphysico-pharmacologically unique entity to maximize their efficacy as aphysical barrier and pharmacologically active agent was leftunaddressed. This and the availability of new forms of bioactive agentswith more than one pharmacological effect provided an incentive toexplore the concept of multifaceted coating composition subject of thisinvention.

SUMMARY OF THE INVENTION

Accordingly, the objective of this invention is to design a multifacetedcoating composition, wherein the bioactive agent has more than onepharmacological attribute for preventing restenosis and also interactswith a functional polymeric barrier to modulate its bioavailability.

This and other goals are achieved by providing an absorbable,amphiphilic, solid copolyester stent coating composition formultifaceted prevention of vascular restenosis through a plurality ofphysicopharmacological modes, which includes at least one bioactivecompound and a segmented/block copolymer having a centralpolyoxyalkylene segment and at least one terminal segment derived fromat least one cyclic monomer, the copolymer having at least one carboxylgroup per chain. Preferably, the polyoxyalkylene segment ispolyoxyethylene and the chain has at least one carboxyl side groupintroduced by free-radically achieved maleation. Alternatively, thechain may include at least one carboxyl end group introduced byacylation of the at least one terminal segment with glutaric anhydride.In a preferred embodiment the at least one bioactive compound is acombination of two bioactive compounds such as an antiangiogeniccompound and a non-steroidal anti-inflammatory drug, an antineoplasticagent and a non-steroidal anti-inflammatory drug, an antineoplasticagent and an anti-platelet aggregation drug, an antiangiogenic agent andanti-platelet aggregation drug, paclitaxel and a non-steroidalanti-inflammatory drug, or lanreotide and trapidil. For the latterembodiment it is preferred that the lanreotide is at least partiallyconjugated ionically with the segmented/block copolymer. In anotherembodiment the at least one bioactive compound is an ionic conjugate ofa basic antiangiogenic peptide and an acidic non-steroidalanti-inflammatory drug. For such embodiment the acidic non-steroidalanti-inflammatory drug may be naproxen. The basic antiangiogenic peptidemay be an LHRH analog or a somatostatin analog. In another embodimentthe at least one bioactive compound is a combination of anantiangiogenic peptide, such as lanreotide, and an anti-plateletaggregation agent, such as trapidil, and the two are ionicallyconjugated with the segmented/block copolymer.

The present invention is also directed to a metallic endovascular stentcoated with the present inventive absorbable stent coating. Further, thepresent invention is directed to an absorbable endovascular stent coatedwith the present inventive absorbable stent coating.

DESCRIPTION OF PREFERRED EMBODIMENTS

The primary objective of the present invention is to provide a coated,endovascular, metallic or polymeric stent comprising one or morebioactive agent that inhibits or minimizes the incidence of vascularrestenosis. A preferred aspect of this invention deals with a metallicstent coated with a compliant, metal-adhering, absorbable copolyesterthat maximizes the mechanical biocompatibility of the metallic stentwith the surrounding vascular tissues. Another preferred aspect of thisinvention deals with an absorbable amphiphilic copolyester coating on ametallic or polymeric endovascular stent with propensity for hydrophilicas well as hydrophobic bioactive agents. A specific aspect of thisinvention deals with a coating made by end-grafting a polyalkyleneglycol and preferably polyethylene glycol with one or more of thefollowing monomer, glycolide, trimethylene carbonate, lactide,ε-caprolactone, p-dioxanone, and 1,5-dioxepan-2-one that is furtherreacted with maleic anhydride in the presence of a free radicalinitiator to introduce anhydride side groups that can be converted tocarboxylic groups. Another preferred aspect of this invention deals witha carboxyl-bearing, absorbable, amphiphilic copolyester capable ofadhering to the surface of a metallic stent as well as ionic conjugationwith basic bioactive agents. Another aspect of this invention deals withan absorbable, amphiphilic, carboxyl-bearing copolyester coating capableof (1) ionic conjugation with basic bioactive agents; and (2) adheringto an absorbable stent through chain interdiffusion at the stent/coatinginterface and/or acid-base interaction. Another preferred aspect of thisinvention deals with a coating comprising one or more bioactive agentthat displays antiangiogenic, anti-inflammatory, and anti-neoplasticeffects. A specific aspect of this invention describes the bioactiveagent as a cyclic octapeptide. A more specific aspect of the inventiondescribes the bioactive agent as cyclic octapeptide somatostatin analogsuch as those cited by Barrie et al., [J. Surg. Res., 55, 446 (1993)] asthe antiangiogenic peptide type, lanreotide. Another specific aspect ofthis invention describes the bioactive agent of a lutenizing humanreleasing hormone (LHRH) analog. A preferred aspect of this inventiondescribes a basic somatostatin or LHRH analog as being present in partor fully as an ionic conjugate of a carboxyl-bearing anti-inflammatorydrug such as naproxen. Another aspect of this invention deals with (1) acombination of an antineoplastic agent, such as paclitaxel or curcumin,and anti-inflammatory drug, such as naproxen; and (2) an antineoplasticagent, such as paclitaxel or curcumin, and an anti-platelet aggregationdrug, such as trapidil. Another aspect of this invention deals with amixture of bioactive agents comprising anti-angiogenic peptide such asone of the somatostatin analogs described above and a non-steroidal,anti-inflammatory drug (NSAID) such as naproxen. Another aspect of thisinvention deals with a mixture of bioactive agents comprising one of thesomatostatin analogs described above and a second agent that is capableof mediating inflammation as well as inhibiting platelet aggregationsuch as trapidil. A specific aspect of this invention deals with acarboxyl-bearing amphiphilic copolyester stent coating, which is atleast partially conjugated with a basic antiangiogenic peptide, such aslanreotide, and trapidil.

Another aspect of this invention deals with a non-absorbable, compliant,metal-adhering coating on an expandable metallic stent such as (1)butyl-methacrylate/methacrylic acid copolymer; and (2) vinyl-acetatebutyl-methacrylate methacrylic acid terpolymer. A preferred aspect ofthis invention deals with one of the aforementioned types ofnon-absorbable coatings containing one or more of the bioactive agentsdescribed above in connection with the absorbable coating. A specificaspect of the non-absorbable coating deals with its use to bind at leastpart of a basic peptide, such as one of those noted above in the form ofan ionic conjugate to control the release of such peptide.

Another aspect of this invention deals with the ionic conjugation of thecarboxyl-bearing coating polymer with the basic peptide, which can beachieved by mixing an aqueous solution of an acetate salt of the peptidewith a solution of the carboxyl-bearing polymer in a water-solublesolvent such as acetonitrile followed by separation of the precipitatedpolymer/peptide ionic conjugate. Alternatively, the peptide solution isallowed to react with an alkali metal salt of the carboxyl-bearingpolymer to yield a precipitate of the polymer-peptide ionic conjugate.

Another aspect of this invention deals with a method of applying asolution of the coating on to a metallic or absorbable polymeric stentusing any of the conventional methods, such as spraying, dipping, andultrasonic atomization of a polymer solution comprising the bioactiveagent or agents, followed by solvent removal by drying.

Additional illustrations of the present invention are given in theExamples discussed below:

EXAMPLE 1 Preparation of an Absorbable, Amphiphilic Copolyesters withCarboxy-Bearing Side-Groups: General Method

In the first step, a predried polyethylene glycol is end-grafted withone or more cyclic monomer (e.g., ε-caprolactone, trimethylenecarbonate, 1-lactide, glycolide, 1,5-dioxepan, and p-dioxanone) by aring-opening mechanism, using a catalytic amount of stannous octoate at150-60° C. for the proper period of time until practically a completeconversion of the monomer(s) is achieved (as determined by GPC). Theresulting amphiphilic polymer is characterized for identity (IR andNMR), thermal properties (DSC), and molecular weight (GPC). In thesecond step, a solution of the amphiphilic polymer in a suitable solvent(e.g., toluene, dioxane) is reacted with maleic anhydride in thepresence of a free-radical initiator (e.g., benzoyl peroxide,azo-bis-butyronitrile) at a suitable temperature (65-80° C.) for anappropriate period of time. The third step entails the treatment of themaleated product from Step 1 with water at 50° C. for 8-16 hours oruntil complete conversion of the anhydride side-groups to carboxylicgroups (as determined by IR). The carboxyl-bearing polymer is thenseparated in a series of steps consisting of solvent evaporation underreduced pressure, rinsing with water, and centrifugation. The resultingproduct is characterized for identity (1R, NMR), thermal properties(DSC), molecular weight (GPC), and carboxyl content (acidimetry).

EXAMPLE 2 Preparation of Absorbable Amphiphilic Copolyester Based onEng-Grafted Polyethylene Glycol (PEG) and Carboxyl-Bearing Side-Groups

Using the general procedure of Example 1, PEG-5000, PEG 8000, andPEG-10,000 are converted to three different amphiphilic copolyesters(AMP-S1 to AMP-S3) as outlined in Table I. Hydrolysis of the anhydridegroup is conducted as in Example 1. The polymers are characterized fortheir identity, molecular weight, and thermal properties as discussed inExample 1. TABLE I Preparation of AMP-S1 to AMP-S3 Copolymer NumberAMP-S1 AMP-S2 AMP-S3 PEG Used, Average Molecular 4600 8000 10,000Weight, Da End-grafting polymerization charge^(a) PEG, moles 0.02 0.0160.001 ε-Caprolactone, moles 1.8 1.8 1.8 1-Lactide, moles 0.2 0.2 0.2Stannous octoate, mmole 0.2 0.2 0.2 Maleation Reaction^(b) Maleicanhydride, moles 0.06 0.048 0.003 Azo-catalyst, g 1.5 1.5 1.5^(a)All reactions are conducted at 150° C. for 16-20 hours, or untilcomplete monomer conversion.^(b)All reactions are conducted at 65° C. for 2-4 hours or untilcompletion (as determined by IR).

EXAMPLE 3 Preparation of Carboxyl-Terminated, Absorbable AmphiphilicCopolyester—General Method

This entails two steps. In the first step, a predried polyethyleneglycol is end-grafted with one or more cyclic monomer (e.g.,ε-caprolactone, trimethylene carbonate, 1-lactide, glycolide,1,5-dioxepan, and p-dioxanone) by a ring-opening mechanism, using acatalytic amount of stannous octoate at 150-60° C. for the proper periodof time until practically a complete conversion of the monomer(s) isachieved (as determined by GPC). The resulting amphiphilic polymer ischaracterized for identity (IR and NMR), thermal properties (DSC), andmolecular weight (GPC). The second step entails the reaction of theend-grafted copolymer from Step 1 with a stoichiometric amount ofglutaric anhydride at 140 to 160° C. for 3-4 hours or until end-groupacylation is practically completed. The resulting polymer ischaracterized for identity (1R, NMR), thermal properties (DSC),molecular weight (GPC), and carboxylic content (acidimetry).

EXAMPLE 4 Preparation of Carboxyl-Terminated Absorbable Copolyester ofDifferent PEGs

Using the general method of Example 3, PEG-2000, PEG-3000 and PEG-5000are converted into three amphiphilic copolyesters (AMP-T1 to AMP-T3) asoutlined in Table II. The carboxyl-terminated copolyesters arecharacterized as described in Example 3. TABLE II Preparation of AMP-T1to AMP-T3 Copolymer Number AMP-T1 AMP-T2 AMP-T3 PEG Used, AverageMolecular 2000 3400 4600 Weight, Da End-grafting polymerizationcharge^(a) PEG, moles 0.05 0.025 0.02 Caprolactone, moles 1.8 1.8 1.81-Lactide, moles 0.2 0.2 0.2 Stannous octoate, mmole 0.2 0.2 0.2Maleation Reaction^(b) Maleic anhydride, moles 0.1 0.05 0.04^(a)All reactions are conducted at 150° C. for 16-20 hours or untilcomplete monomer conversion.^(b)All reactions are conducted at 65° C. for 2-4 hours or untilcomplete consumption of the anhydride is realized (as determined by IR).

EXAMPLE 5 Preparation of Bioactive AMP-S1 Formulation with Lanreotideand Trapidil Hydrochloride and Stent Coating Therewith

This entails two steps. In the first step, AMP-S 12 (1 g) from Example 2is dissolved in acetonitrile (10 mL) and neutralized with aqueous sodiumbicarbonate. To this is added, while stirring, a solution of lanreotideacetate (0.1 g) in water (0.5 mL) and mixing is continued for 1 hour at25° C. to complete the formation of the AMP-S—lanreotide ionicconjugate. The latter was lyophilized to rid of the liquid components.The solid ionic conjugate is then redissolved in methylene chloride (10mL) and a finely divided trapidil hydrochloride (0.1 g) is added whilestirring. The solution of the bioactive formulation isfilter-sterilized. The sterilized solution can then be applied to themetallic stent (or absorbable stent using non-solvent for stent uponpreparing the sterile solution) by standard techniques (ultrasonicspraying, dipping). The coated stent is dried in a laminar flow hoodprior to packaging.

EXAMPLE 6 Preparation of a Bioactive AMP-T1 with Lanreotide and Trapidiland Stent Coating Therewith

This is pursued under similar conditions to those described in Example 5with the exception of substituting AMP-T1 for AMP-S1.

EXAMPLE 7 Preparation of Bioactive AMP-S1 Ionically Conjugated withLanreotide and Trapidil

AMP-S1 (1 g) from Example 2 is dissolved in acetonitrile (10 mL) andneutralized with aqueous sodium bicarbonate. To this is added, whilestirring, a solution of lanreotide acetate (0.08 g) in water (0.5 mL)followed by a solution of trapidil hydrochloride (0.002 g) in water (0.2mL). Mixing is continued for 1 hour at 25° C. to complete theformulation of AMP-S1 ionic conjugate with lanreotide and trapidil. Thereaction product is lyophilized to yield the solid conjugate.

EXAMPLE 8 Preparation of Ionic Conjugates of Lanreotide and Naproxen

A solution of lanreotide acetate (1 mmole, based on the active freebase) in water (2.5 mL) is mixed with naproxen in the free acid form (1mmole). The mixture of the two compounds is stirred at 25° C. under anitrogen atmosphere until a clear solution is obtained. The latter isthen lyophilized to produce a ready-to-use solid conjugate.

Although the present invention has been described in connection with thepreferred embodiments, it is to be understood that modifications andvariations may be utilized without departing from the principles andscope of the invention, as those skilled in the art will readilyunderstand. Accordingly, such modifications may be practiced within thescope of the following claims. Moreover, Applicants hereby disclose allsub-ranges of all ranges disclosed herein. These sub-ranges are alsouseful in carrying out the present invention.

1. An absorbable, amphiphilic, solid copolyester stent coatingcomposition for multifaceted prevention of vascular restenosis through aplurality of physicopharmacological modes comprising at least onebioactive compound and a segmented/block copolymer comprising a centralpolyoxyalkylene segment and at least one terminal segment derived fromat least one cyclic monomer, the copolymer further comprising at leastone carboxyl group per chain.
 2. An absorbable stent coating as setforth in claim 1 wherein the polyoxyalkylene segment comprisespolyoxyethylene and wherein the chain comprises at least one carboxylside group introduced by free-radically achieved maleation.
 3. Anabsorbable stent coating as set forth in claim 1 wherein thepolyoxyalkylene segment comprises polyoxyethylene and wherein the chaincomprises at least one carboxyl end group introduced by acylation of theat least one terminal segment with glutaric anhydride.
 4. An absorbablestent coating as set forth in claim 1 wherein the at least one bioactivecompound comprises an antiangiogenic compound and a non-steroidalanti-inflammatory drug.
 5. An absorbable stent coating as set forth inclaim 1 wherein the at least one bioactive compound comprises anantineoplastic agent and a non-steroidal anti-inflammatory drug.
 6. Anabsorbable stent coating as set forth in claim 1 wherein the at leastone bioactive compound comprises an antineoplastic agent and ananti-platelet aggregation drug.
 7. An absorbable stent coating as setforth in claim 1 wherein the at least one bioactive compound comprisesan antiangiogenic agent and anti-platelet aggregation drug.
 8. Anabsorbable stent coating as set forth in claim 1 wherein the at leastone bioactive compound comprises paclitaxel and a non-steroidalanti-inflammatory drug.
 9. An absorbable stent coating as set forth inclaim 1 wherein the at least one bioactive compound comprises lanreotideand trapidil.
 10. An absorbable stent coating as set forth in claim 9wherein the lanreotide is at least partially conjugated ionically withthe segmented/block copolymer.
 11. An absorbable stent coating as setforth in claim 1 wherein the at least one bioactive compound comprisesan ionic conjugate of a basic antiangiogenic peptide and an acidicnon-steroidal anti-inflammatory drug.
 12. An absorbable stent coating asset forth in claim 11 wherein the acidic non-steroidal anti-inflammatorydrug comprises naproxen.
 13. An absorbable stent coating as set forth inclaim 12 wherein the basic antiangiogenic peptide comprises an LHRHanalog.
 14. An absorbable stent coating as set forth in claim 12 whereinthe basic antiangiogenic peptide comprises a somatostatin analog.
 15. Anabsorbable stent coating as set forth in claim 1 wherein the at leastone bioactive compound comprises an antiangiogenic peptide and ananti-platelet aggregation agent and wherein the antiangiogenic peptideand the anti-platelet aggregation agent are ionically conjugated withthe segmented/block copolymer.
 16. An absorbable stent coating as in setforth in claim 15 wherein the antiangiogenic peptide compriseslanreotide and the anti-platelet aggregation agent comprises trapidil.17. A metallic endovascular stent coated with the absorbable stentcoating of claim
 1. 18. An absorbable endovascular stent coated with theabsorbable stent coating of claim 1.